What are the pharmacokinetics of paracetamol (acetaminophen)?

Pharmacokinetics of Paracetamol

Absorption

Paracetamol is rapidly absorbed from the gastrointestinal tract following oral administration, with systemic bioavailability ranging from 70-90% depending on the dose. 1, 2

• The rate of absorption is predominantly dependent on the rate of gastric emptying, as absorption occurs primarily in the small intestine by passive diffusion 2, 3
• Peak plasma concentrations are typically achieved within 30-60 minutes after oral administration in fasting conditions 1
• Gastric emptying (and thus absorption) is delayed by food, propantheline, pethidine, and diamorphine, while it is enhanced by metoclopramide 2
• Effervescent formulations result in more rapid drug absorption and onset of action compared to conventional tablets 1
• Rectal absorption differs significantly from oral administration, characterized by slow and irregular absorption of the active substance 1

Distribution

Paracetamol distributes rapidly and evenly throughout most tissues and fluids with a volume of distribution of approximately 0.9 L/kg. 2

• Only 10-20% of the drug binds to red blood cells 2
• Plasma protein binding is very low, which accounts for the minimal risk of drug interactions 1
• Therapeutic plasma concentrations range from 5-20 μg/mL, far below the toxic threshold of 150 μg/mL 4

Metabolism

Paracetamol is extensively metabolized predominantly in the liver, with the major metabolites being sulphate and glucuronide conjugates. 2, 4

• At therapeutic doses, 85-95% of the drug is excreted in urine within 24 hours as: approximately 4% unchanged paracetamol, 55% glucuronide conjugate, 30% sulphate conjugate, and 4% each as mercapturic acid and cysteine conjugates 2
• A minor fraction (normally <5%) is converted via P450 enzymes to a highly reactive alkylating metabolite (N-acetyl-p-benzoquinone imine, NAPQI), which is normally inactivated by conjugation with reduced glutathione 2, 4, 5
• In overdose situations (>2,000 mg/kg), hepatic glutathione stores become depleted, leaving the toxic intermediate free to bind to vital cell constituents and cause hepatic necrosis 4, 5

Elimination

The plasma half-life in healthy subjects ranges from 1.9-2.5 hours, with total body clearance of 4.5-5.5 mL/kg/min. 2

• At therapeutic concentrations, the pharmacokinetics are linear—independent of dose and constant with repeated administration 1
• The plasma half-life is usually normal in patients with mild chronic liver disease but is prolonged in those with decompensated liver disease 2
• The plasma half-life is shortened in patients taking anticonvulsants due to enzyme induction 2
• Age has little effect on plasma half-life, though clearance may be reduced in elderly patients without necessitating dose adjustment 1

Special Populations

Paracetamol is the non-opioid analgesic of choice in elderly persons and patients with chronic renal insufficiency, typically not requiring dose reduction despite reduced clearance. 1

• Bioavailability is not impaired in patients with chronic benign liver diseases, but the agent is contraindicated in those with hepatic insufficiency 1
• The drug can be used safely during pregnancy and lactation 1
• In children, pharmacokinetics are influenced by age, with an oral dose of 15 mg/kg every 4 hours (up to 60 mg/kg/day total) typically sufficient for analgesic or antipyretic effects 1

Clinical Dosing Implications

In adults, the optimum single dose is 1 gram, with a maximum daily dosage of 4 grams, consistent with analgesic activity duration of approximately 6 hours. 1

• There is no direct correlation between serum concentrations of paracetamol and its analgesic or antipyretic effect within the therapeutic range 1
• For patients with risk factors for hepatotoxicity (such as chronic alcohol use), maximum daily dose should be limited to 2,000-3,000 mg 6